ADMINISTRATIVE SUPPLEMENT REQUEST ? Alzheimer's disease-like pathology in aging marmosets? ABSTRACT A recent study has demonstrated that the brain of older marmosets presents some of the hallmarks of Alzheimer's disease (AD), abnormal hyperphosphorylated Tau and cortical deposition of ?-amyloid (Rodriguez-Callejas et al., 2016). These findings suggest that the marmoset may naturally undergo AD-like pathogenesis with age, making this species a strong candidate for a nonhuman primate (NHP) model of AD. However, the functional consequences of these degenerative hallmarks are completely unknown. Behavioral assays are critically needed to determine whether AD-like neuropathology is associated with severe behavioral and cognitive changes in this species. Our funded studies aim to characterize changes in behavior, cognitive function, stress reactivity and fine motor function in marmosets of both sexes followed longitudinally for 4 years before postmortem analyses of brain tissues in the same animals. We are therefore in a unique position to determine whether the presence of neuropathology is associated with specific age-related phenotypic changes. In addition, because the parent grant is focused on sex differences in neurocognitive aging, we will be able to determine whether the female marmoset, like the woman, is at greater risk to develop neuropathology and associated behavioral deficits. This supplemental application will broaden our current assessments with behavioral, physiological and histological measures designed to specifically capture AD-like symptomology. We will (1) complement our behavioral assays with assessments of circadian activity, affect, and cognitive function specifically designed to capture AD-like symptomology; (2) measure peripheral neuroinflammatory and metabolic markers relevant to AD and (3) assess Tau and microglia alterations as well as patterns of gene expression in specific brain areas in the same animals postmortem. The studies described in this supplemental request should establish the marmoset as a new NHP model of AD, in which some of the hallmarks of the disease develop naturally with age. We believe that future studies in this short-lived primate will offer new possibilities for the assessment of the progression of neurocognitive impairment as it relates to neuropathology (neuroimaging assessments), the identification of new biomarkers of AD, the testing of causal factors (e.g, sleep fragmentation) and the design of new therapeutics tailored to each sex.